scholarly journals Investigating Antisense Transcription at the HTT Locus

2022 ◽  
Author(s):  
Eugeny A. Elisaphenko ◽  
Anastasia A. Malakhova
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Intracellular Trafficking ◽  
Gene Expression Regulation ◽  
Antisense Transcription ◽  
Dependent Manner ◽  
Rna Seq ◽  
Antisense Transcripts ◽  
Cell Processes ◽  
Different Parts

Antisense transcription is an important mechanism of gene expression regulation. Antisense RNAs play a role in mRNA processing, translation and epigenetic modifications of DNA and histones in the locus of their origin, leading to gene silencing. HTT is a widely expressed gene, the mutation of which causes Huntington’s disease. The product of the gene plays an important role in many cell processes, such as intracellular trafficking, cell division, autophagy, and others. An antisense transcription has been found at the HTT 5’-region. The HTT-AS gene has been reported to affect HTT expression in a Dicer-dependent manner. In this study, we analyzed extensive data from RNA-seq experiments for antisense transcription at the HTT locus. Antisense transcripts corresponding to the HTT-AS gene were not found. However, we revealed a number of antisense transcripts in different parts of the locus that may take part in the regulation and functioning of the HTT gene. Keywords: antisense transcription, HTT-AS, HTTregulation, Huntington’s disease

scholarly journals Single-nucleus RNA-seq reveals dysregulation of striatal cell identity due to Huntington’s disease mutations

2020 ◽  
Author(s):  
Sonia Malaiya ◽  
Marcia Cortes-Gutierrez ◽  
Brian R. Herb ◽  
Sydney R. Coffey ◽  
Samuel R.W. Legg ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cell Types ◽  
Transcriptional Networks ◽  
Rna Seq ◽  
Cell Type ◽  
Cell Identity ◽  
Transcriptional Changes ◽  
Cell Type Specific

ABSTRACTHuntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (Htt) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4,524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, HttQ175/+, and from wildtype controls. We used 14-15-month-old mice, a time point roughly equivalent to an early stage of symptomatic human disease. Cell type distributions indicated selective loss of D2 MSNs and increased microglia in aged HttQ175/+ mice. Thousands of differentially expressed genes were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell typespecific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes. Typically, these genes were repressed in their primary cell type, yet de-repressed in other striatal cell types. Integration with existing epigenomic and transcriptomic data suggest that partial loss-of-function of the Polycomb Repressive Complex 2 (PRC2) may underlie many of these transcriptional changes, leading to deficits in the maintenance of cell identity across virtually all cell types in the adult striatum.

scholarly journals Mutant Huntingtin Affects Diabetes and Alzheimer’s Markers in Human and Cell Models of Huntington’s Disease

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 962 ◽  
Author(s):  
Gepoliano Chaves ◽  
John Stanley ◽  
Nader Pourmand
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genome Wide Association Study ◽  
Cell Model ◽  
Statistical Significance ◽  
Mutant Huntingtin ◽  
Rna Seq ◽  
Genome Wide ◽  
A Genome ◽  
Reliable Model

A higher incidence of diabetes was observed among family members of individuals affected by Huntington’s Disease with no follow-up studies investigating the genetic nature of the observation. Using a genome-wide association study (GWAS), RNA sequencing (RNA-Seq) analysis and western blotting of Rattus norvegicus and human, we were able to identify that the gene family of sortilin receptors was affected in Huntington’s Disease patients. We observed that less than 5% of SNPs were of statistical significance and that sortilins and HLA/MHC gene expression or SNPs were associated with mutant huntingtin (mHTT). These results suggest that ST14A cells derived from R. norvegicus are a reliable model of HD, since sortilins were identified through analysis of the transcriptome in these cells. These findings help highlight the genes involved in mechanisms targeted by diabetes drugs, such as glucose transporters as well as proteins controlling insulin release related to mHTT. To the best of our knowledge, this is the first GWAS using RNA-Seq data from both ST14A rat HD cell model and human Huntington’s Disease.

Facts and figures about Huntington’s disease

2020 ◽  
pp. 1-8 ◽  
Author(s):  
Oliver Quarrell
Keyword(s):  
North America ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Original Description ◽  
The World ◽  
History Of ◽  
Different Parts

This chapter gives a brief history of Huntington’s disease (HD) starting with the original description by George Huntington. The prevalence of HD is discussed together with data variations in different parts of the world. For example the incidence of HD in Europe and North America is approximately 1 person in 10,000. Apart from humans, no other animal naturally develops HD. The condition can start at almost any age but it is more frequent in midlife. The duration of the disease can be very variable but 20 years is often given as an approximate average.

scholarly journals Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3172
Author(s):  
Tatiana Brustovetsky ◽  
Rajesh Khanna ◽  
Nickolay Brustovetsky
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mitochondrial Dynamics ◽  
Neuroprotective Effect ◽  
Mitochondrial Fission ◽  
Postmortem Brain ◽  
Mitochondrial Morphology ◽  
Dependent Manner ◽  
Striatal Neurons ◽  
Human Neurons

Mitochondrial morphology and motility (mitochondrial dynamics) play a major role in the proper functioning of distant synapses. In Huntington’s disease (HD), mitochondria become fragmented and less motile, but the mechanisms leading to these changes are not clear. Here, we found that collapsin response mediator protein 2 (CRMP2) interacted with Drp1 and Miro 2, proteins involved in regulating mitochondrial dynamics. CRMP2 interaction with these proteins inversely correlated with CRMP2 phosphorylation. CRMP2 was hyperphosphorylated in postmortem brain tissues of HD patients, in human neurons derived from induced pluripotent stem cells from HD patients, and in cultured striatal neurons from HD mouse model YAC128. At the same time, CRMP2 interaction with Drp1 and Miro 2 was diminished in HD neurons. The CRMP2 hyperphosphorylation and dissociation from Drp1 and Miro 2 correlated with increased fission and suppressed motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Thr 509/514 and Ser 522 and rescued CRMP2’s interaction with Drp1 and Miro 2. This was accompanied by reduced mitochondrial fission and enhanced mitochondrial motility. Additionally, (S)-LCM exerted a neuroprotective effect in YAC128 cultured neurons. Thus, our data suggest that CRMP2 may regulate mitochondrial dynamics in a phosphorylation-dependent manner and modulate neuronal survival in HD.

scholarly journals Heat Shock Factor 1 Directly Regulates Postsynaptic Scaffolding PSD-95 in Aging and Huntington’s Disease and Influences Striatal Synaptic Density

2021 ◽  
Vol 22 (23) ◽  
pp. 13113
Author(s):  
Nicole Zarate ◽  
Taylor A. Intihar ◽  
Dahyun Yu ◽  
Jacob Sawyer ◽  
Wei Tsai ◽  
...  
Keyword(s):  
Heat Shock ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Regulatory Elements ◽  
Scaffolding Protein ◽  
Heat Shock Factor 1 ◽  
Dependent Manner ◽  
Regulatory Relationship ◽  
Direct Role ◽  
Protein Levels

PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington’s disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute reduction in cell lines and mice decreased PSD-95 expression. Furthermore, Hsf1(+/−) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.

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